NeuroVoices: Crystal Proud, MD, on SMA Awareness Month, Advances in Research and Treatments

Crystal Proud, MD

Every August, those around the globe come together to raise awareness for spinal muscular atrophy (SMA), a severe neuromuscular disease considered to be the leading genetic cause of infant death. The most common form of SMA, 5q SMA, makes up more than 95% of all cases and is an autosomal recessive disorder caused by homozygous deletion or deletion and mutation of the alleles of the survival motor neuron 1 (SMN1) gene.

Over the years, there has been immense progress in the detection and understanding of SMA, which has led to the first disease-specific treatments, including a gene therapy, which came about in 2019. These have not only transformed the lives of patients with SMA, but also improved motor function, extended survival rates, and allowed patients to achieve developmental milestones that were previously unattainable. The introduction of these therapies has also shifted the focus of care solely from managing symptoms to actively improving long-term outcomes and quality of life.

In efforts to continue to raise awareness, NeurologyLive® sat down with SMA expert Crystal Proud, MD, to discuss a few SMA topics, including an update on drug development, advances in research, and the evolution of clinical trials. Proud, who serves as the director of neurology and neuromuscular medicine at the Children’s Hospital of the King’s Daughters in Norfolk, Virginia, gave thoughts on the improvements in newborn screening and where efforts could be directed towards to enhance the access to treatments. She also spoke on the underrecognized aspects of SMA that require more attention, particularly as patients are now living longer due to improved treatments. Specifically, she spoke on cognitive impacts, the incidence of autism, and concerns with early-onset scoliosis.

NeurologyLive: What are some of the positive awareness efforts we’ve seen in SMA?

Crystal Proud, MD: Oh, I think recently, we've done a nice job of raising awareness about newborn screening. Now we screen for the possibility of babies having SMA in all 50 states, which is a huge accomplishment. However, this still leaves an estimated 5% of children undiagnosed through the newborn screening program, and those children will be diagnosed based on symptoms. So, we still need clinicians to consider the possibility of spinal muscular atrophy in a child presenting with weakness. That's something we need to make sure we bring to the forefront. It’s been an exciting time in clinical research, but our job is not done yet. I think we’re doing a great job of highlighting the progress we've made, but we still require comprehensive, multidisciplinary care and ongoing efforts to really optimize the outcomes for the kids and adults impacted by SMA.

How can we improve the process of newborn screening to ensure that patients—infants especially—gain access to the treatments they may need?

It's important and critical that we recognize that every day a child with SMA goes untreated is a day where we could potentially lose very valuable motor neurons, and those motor neurons can impact the long-term functional outcomes of our patients. If we want to optimize their long-term motor function, their overall abilities, their capacity for independence, and their skill development, then the goal should be to treat them as soon as possible. The barriers to that are numerous. Even with newborn screening in place, there can be delays in getting samples to the lab. Different state labs have varying processing times—some process daily, while others batch their tests together. This can impact the timing of those results reaching the clinician.

Then, once we receive those tests, we need to confirm them, usually with a secondary test that confirms the diagnosis and often gives us the estimated copy number, which can play a role in some of the opportunities we might present, whether it be a commercially available treatment or a research protocol they can enter into. The next step is obviously authorizing treatment after it’s prescribed, and then getting that treatment shipped to the location where it will be administered. Each of these steps can prove to be a barrier to timely treatment, so if we examine each closely, we’ll hopefully be able to cut down on the time it takes from diagnosis to intervention.

Are there aspects of SMA that are underrecognized or deserve more attention?

Over the years, we've done a great job of optimizing motor outcomes and survival for our patients. As we see these kids survive longer, our goals are shifting—we really want them to thrive. But in an era where we now have numerous treatments available and sometimes combination treatments, we are approaching new challenges. Several of these have been highlighted recently, and I think this is where our research and investigation need to go further. We know that there are some cognitive impacts and other skills that might be more challenging for our patients with SMA. There seems to be a new recognition of a subset of our patients with SMA having a higher incidence of autism, for example. We need to explore that, characterize it better, and try to understand why that is.

Additionally, despite early treatment and advances in motor function, we are still seeing very early scoliosis develop. We thought that if we could get these kids stronger, we might be able to avoid surgical intervention, but the opposite has happened. We’re seeing an incredible increase in strength in our kids, but they’re still developing significant spinal curvatures that require surgical intervention earlier than before. So, we have to ask ourselves why this is happening and what we can do to address and assess it earlier. Part of that is awareness—awareness of the social, emotional, and cognitive developments of these kids. We need to screen more for developmental milestones, social milestones, and verbal milestones, and get them into therapies if they’re not meeting those. We might even need to pursue further diagnostic testing, like neuropsychological assessments. Additionally, we need to make sure we are evaluating orthopedic possibilities and keeping those in mind as well.

What are some of the main updates in drug development for SMA?

I'm really excited about where research is headed for spinal muscular atrophy. Now we are going beyond advancing motor function and survival to really optimizing the long-term outcomes for our patients. There are clinical trials looking at combination therapies, higher doses of one of our currently available treatments, nusinersen, and even going beyond the motor neuron to look at the neuromuscular junction and muscle. These are all strategies currently underway to optimize long-term outcomes for our patients. I think these are the next round of things to be excited about when it comes to therapeutic options for our patients. I believe the days of offering just one treatment are gone. We will likely advance our patients’ care by prescribing multiple interventions with different therapeutic mechanisms of action to provide the best care and long-term outcomes.

How have clinical trials continued to evolve for SMA?

I’m excited that we recognize we’re not done yet in SMA. Despite having several approved treatments, it’s not stopping there—we’ve really just begun. Our clinical trials right now are focusing on continued improvements, whether through combining different mechanisms of action, optimizing dosing or the administration route for a particular therapy, or looking beyond the motor neuron to provide a holistic approach to treatment for SMA. I think we’re continuing to challenge ourselves and our researchers to do more—we’re really just getting started.